1. Field of the Invention
The present invention relates to compounds that bind with high affinity and/or specificity to kappa opioid receptors.
2. Background of the Invention
The study of compounds exerting their actions via the opioid receptor system has continued for nearly eight decades.1 Though this has been a broad effort, the fundamental driving force for this endeavor relates to the elimination or reduction of the side-effect profile produced by the most frequently used or abused opiates morphine (1) and heroin (2). The wealth of knowledge accumulated in this time is enormous and includes examples of milestone discoveries commensurate with its breadth from the original concept of an opiate receptor2 to the more recent cloning of three individual opioid receptor subtypes mu3-5 delta6,7 and kappa.8-10 Belonging to the superfamily of G protein-coupled receptors (GPCR), postulated to possess seven helical transmembrane (7TM) spanning regions, they are now known to be anatomically distributed in both the central and peripheral nervous systems and aside from modulation of pain are intimately involved in a diversity of biological events ranging from of the modulation of immune response11 to hibernation.12 
Among the many side effects produced by compounds 1 and 2, addiction, tolerance and respiratory depression are of greatest concern when heroin abuse is considered. Though its use waned in the late 70s, increases in both the purity and availability of this drug have promoted a serious resurgence of illegal use. In the study and treatment of substance abuse, antagonists for the opioid receptors like naltrexone (3) have played a prominent role.13,14 In recent years, researchers studying the physiological mechanisms underlying addiction have sought antagonists selective for each of the three opioid receptor subtypes mu, delta and kappa. Extensive research efforts along these lines lead to the discovery of several such compounds with examples including cyprodime (mu, 4)15, naltrindole (delta, 5)16 and norbinaltorphimine (kappa, 6).17 Of the three, the kappa receptor has only begrudgingly yielded antagonists and, of the known examples, all stem from modification of the prototype, norbinaltorphimine (nor-BNI, 6) Portoghese in his pioneering work provided not only the second and third generation kappa antagonists 5xe2x80x2-[(N2-butylamidino)methyl]naltrindole (7)18 and C5xe2x80x2-guanidinylnaltrindole (GNTI, 8)19 but also convincing evidence that the Glu297 residue in transmembrane helix 6 of the kappa receptor is the principle address site influencing the kappa selectivity found in 6-8. In terms of the message address concept20 as applied by Portoghese to opioid small-molecules, it is the pendant amine functionality (noted by asterisks in the chart) present in 6-8 that functions as the kappa address element by interacting with the Glu297 residue which is present in the kappa but not in the mu receptor.
In terms of substance abuse treatment, antagonists selective for the kappa receptor have been the least studied primarily due to the limited bio-availability of 6 and its analogs. However, mounting evidence that the endogenous kappa opioid system opposes the actions of mu agonists like 2 suggests that antagonists selective for the kappa receptor could suppress or eliminate the symptoms of withdrawal which arise from an overactive kappa receptor system and thus could promote abstinence and prevent relapse. Therefore, the development of novel kappa antagonists possessing improved pharmacokinetic profiles would be of great value.21-25 
As is obvious from the examples above, the morphinan substructure of 3 has served as the preeminent template upon which selective antagonists have been constructed. Contrary to these efforts, our work in this field started from the relatively unstudied N-substituted trans-(3,4)-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid antagonist discovered by Zimmerman et al in the late 70""s, (e.g. 9).26-33 These compounds were novel opioid antagonists because their intrinsic antagonist activity was not mediated by the structure of their N-substituent (i.e. the N-methyl and N-cyclopropylmethyl analogs in the phenylpiperidine series are both pure antagonists). Instead, the antagonist activity in the phenylpiperidine series appears to arise from the 3,4-dimethyl substituents. Early investigations in the 4-phenylpiperidine series suggested that their antagonist activity was mediated through a phenylequatorial mode of binding at opioid receptors. This hypothesis was recently confirmed by the demonstration of potent though non-selective opioid antagonist activity in N-phenethyl-9xcex2-methyl-5-(3-hydroxyphenyl)morphan (10), a conformationally rigid analog of N-phenethyl-trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (9).34 
It is an object of the invention to provide compounds which bind to kappa opioid receptors with high affinity.
It is another object of the invention to provide compounds which bind to kappa opioid receptors with high specificity.
It is another object of the invention to provide compounds which bind to kappa opioid receptors with high affinity and specificity.
The objects of the present invention, and others, are accomplished with compounds represented by the formula: 
wherein R1 is C2-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C1-8 alkylaryl or one of the following groups: 
R2 is a member selected from the group consisting of formulae (a)-(pp): 
X is NR, O or S;
Y is OH, OR9, C1-8 alkyl, F, Cl, or CF3;
R is hydrogen, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C1-8 alkylaryl, CO2R9 
W is a member selected from the group consisting of: H, OH, COOR9; amino, xe2x80x94NR3SO2R9 and xe2x80x94NR3CO2R9;
Z is NR3 or O;
n is 1, 2 or 3;
m is 1, 2, 3 or 4;
j is 2, 3 or 4;
k is 1 or 2;
R3 is hydrogen, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, or C1-8 alkylaryl;
R4 is hydrogen, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, or C1-8 alkylaryl;
R5 and R6 are each independently, hydrogen, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, or C1-8 alkylaryl;
R7 and R8 are each independently, hydrogen, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, or C1-8 alkylaryl; and
R9 is C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, or C1-8 alkylaryl;
and the use of these compounds in pharmaceutical compositions for the treatment of disease states that are ameliorated by binding of the kappa opioid receptor such as heroin or cocaine addictions.